title: Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II.
abstract: The anti-hyperglycaemic drug metformin has important anticancer properties as shown by the direct inhibition of cancer cells proliferation. Tumor cells avidly use glucose as a source for energy production and cell building blocks. Critical to this phenotype is the production of glucose-6-phosphate (G6P), catalysed by hexokinases (HK) I and II, whose role in glucose retention and metabolism is highly advantageous for cell survival and proliferation. Here we show that metformin impairs the enzymatic function of HKI and II in Calu-1 cells. This inhibition virtually abolishes cell glucose uptake and phosphorylation as documented by the reduced entrapment of ¹⁸F-fluorodeoxyglucose. In-silico models indicate that this action is due to metformin capability to mimic G6P features by steadily binding its pocket in HKII. The impairment of this energy source results in mitochondrial depolarization and subsequent cell death. These results could represent a starting point to open effective strategies in cancer prevention and treatment.
authors.affiliation: Department of Internal Medicine-DIMI, University of Genova, 16132 Genova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Salani
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marini
authors.forename: Alberto Del
authors.initials: AD
authors.lastname: Rio
authors.forename: Silvia
authors.initials: S
authors.lastname: Ravera
authors.forename: Michela
authors.initials: M
authors.lastname: Massollo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Orengo
authors.forename: Adriana
authors.initials: A
authors.lastname: Amaro
authors.forename: Mario
authors.initials: M
authors.lastname: Passalacqua
authors.forename: Sara
authors.initials: S
authors.lastname: Maffioli
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
authors.forename: Renzo
authors.initials: R
authors.lastname: Cordera
authors.forename: Davide
authors.initials: D
authors.lastname: Maggi
authors.forename: Gianmario
authors.initials: G
authors.lastname: Sambuceti
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D006593:Hexokinase / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D006593:Hexokinase; D005947:Glucose